Distinct Regions of the slo Subunit Determine Differential BK Ca Channel Responses to Ethanol

Pengchong Liu, Jianxi Liu, Weihua Huang, Ming D. Li, Alejandro Dopico

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Background: Ethanol at clinically relevant concentrations increases BK Ca channel activity in dorsal root ganglia neurons, GH3 cells, and neurohypophysial terminals, leading to decreases in cell excitability and peptide release. In contrast, ethanol inhibits BK Ca channels from aortic myocytes, which likely contributes to alcohol-induced aortic constriction. The mechanisms that determine differential BK Ca channel responses to ethanol are unknown. We hypothesized that nonconserved regions in the BK ca channel-forming subunit (slo) are major contributors to the differential alcohol responses of different BK Ca channel phenotypes. Methods: We constructed chimeras by interchanging the core and the tail domains of two BK Ca channel-forming subunits (mslo and bslo) that, after expression, differentially respond to ethanol (activation and inhibition, respectively), and studied ethanol action on these mbslo and bmslo chimeric channels using single-channel, patch-clamp techniques. Results and Conclusion: Data from cell-free membranes patches demonstrate that the activity of channels that share a mslo-type core-linker (wt mslo and the mbslo chimera) is consistently and significantly potentiated by acute exposure to ethanol. Thus, a mslo tail is not necessary for ethanol potentiation of slo channels. In contrast, the activity of channels that share a bslo-type core-linker (wt bslo and the bmslo chimera) display heterogenous responses to ethanol: inhibition (in the majority of cases), refractoriness, or activation. Overall, our data indicate that the slo core-linker is a critical region likely contributing to the differential responses of BK Ca channels to ethanol.

Original languageEnglish (US)
Pages (from-to)1640-1644
Number of pages5
JournalAlcoholism: Clinical and Experimental Research
Volume27
Issue number10
DOIs
StatePublished - Oct 1 2003

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Large-Conductance Calcium-Activated Potassium Channels
Ethanol
Chemical activation
Alcohols
Clamping devices
Spinal Ganglia
Patch-Clamp Techniques
Constriction
Muscle Cells
Neurons
Cell Membrane
Membranes
Phenotype
Peptides

All Science Journal Classification (ASJC) codes

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

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Distinct Regions of the slo Subunit Determine Differential BK Ca Channel Responses to Ethanol . / Liu, Pengchong; Liu, Jianxi; Huang, Weihua; Li, Ming D.; Dopico, Alejandro.

In: Alcoholism: Clinical and Experimental Research, Vol. 27, No. 10, 01.10.2003, p. 1640-1644.

Research output: Contribution to journalArticle

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AU - Dopico, Alejandro

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N2 - Background: Ethanol at clinically relevant concentrations increases BK Ca channel activity in dorsal root ganglia neurons, GH3 cells, and neurohypophysial terminals, leading to decreases in cell excitability and peptide release. In contrast, ethanol inhibits BK Ca channels from aortic myocytes, which likely contributes to alcohol-induced aortic constriction. The mechanisms that determine differential BK Ca channel responses to ethanol are unknown. We hypothesized that nonconserved regions in the BK ca channel-forming subunit (slo) are major contributors to the differential alcohol responses of different BK Ca channel phenotypes. Methods: We constructed chimeras by interchanging the core and the tail domains of two BK Ca channel-forming subunits (mslo and bslo) that, after expression, differentially respond to ethanol (activation and inhibition, respectively), and studied ethanol action on these mbslo and bmslo chimeric channels using single-channel, patch-clamp techniques. Results and Conclusion: Data from cell-free membranes patches demonstrate that the activity of channels that share a mslo-type core-linker (wt mslo and the mbslo chimera) is consistently and significantly potentiated by acute exposure to ethanol. Thus, a mslo tail is not necessary for ethanol potentiation of slo channels. In contrast, the activity of channels that share a bslo-type core-linker (wt bslo and the bmslo chimera) display heterogenous responses to ethanol: inhibition (in the majority of cases), refractoriness, or activation. Overall, our data indicate that the slo core-linker is a critical region likely contributing to the differential responses of BK Ca channels to ethanol.

AB - Background: Ethanol at clinically relevant concentrations increases BK Ca channel activity in dorsal root ganglia neurons, GH3 cells, and neurohypophysial terminals, leading to decreases in cell excitability and peptide release. In contrast, ethanol inhibits BK Ca channels from aortic myocytes, which likely contributes to alcohol-induced aortic constriction. The mechanisms that determine differential BK Ca channel responses to ethanol are unknown. We hypothesized that nonconserved regions in the BK ca channel-forming subunit (slo) are major contributors to the differential alcohol responses of different BK Ca channel phenotypes. Methods: We constructed chimeras by interchanging the core and the tail domains of two BK Ca channel-forming subunits (mslo and bslo) that, after expression, differentially respond to ethanol (activation and inhibition, respectively), and studied ethanol action on these mbslo and bmslo chimeric channels using single-channel, patch-clamp techniques. Results and Conclusion: Data from cell-free membranes patches demonstrate that the activity of channels that share a mslo-type core-linker (wt mslo and the mbslo chimera) is consistently and significantly potentiated by acute exposure to ethanol. Thus, a mslo tail is not necessary for ethanol potentiation of slo channels. In contrast, the activity of channels that share a bslo-type core-linker (wt bslo and the bmslo chimera) display heterogenous responses to ethanol: inhibition (in the majority of cases), refractoriness, or activation. Overall, our data indicate that the slo core-linker is a critical region likely contributing to the differential responses of BK Ca channels to ethanol.

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